Abstract

Background Although autopsy studies demonstrate that most STEMI are caused by rupture of pre-existing lipid core plaque (LCP), it has not been possible to identify LCP in vivo. A novel intracoronary NIRS catheter has made it possible to detect LCP in patients.

Methods We performed NIRS within the culprit vessels of 20 patients with acute STEMI and compared the STEMI culprit findings to findings in nonculprit segments of the artery and to findings in autopsy control segments. Culprit and control segments were analyzed for the maximum lipid core burden index in a 4-mm length of artery (maxLCBI4mm).

Each year in the United States alone, more than 1 million individuals experience a myocardial infarction or sudden cardiac death (1). These unexpected and often catastrophic events occur despite a well-developed understanding of the pathophysiology of the disorders (2–4). Post-mortem findings have proven that most cases of sudden coronary death and fatal myocardial infarction are caused by rupture of a vulnerable atherosclerotic plaque leading to occlusive thrombosis (2–8). These autopsy studies have also demonstrated that the underlying culprit lesion is frequently a large lipid core plaque (LCP) (2,3,5–8).

In 1980, DeWood et al. (9) obtained data in vivo demonstrating thrombus at the culprit site in patients experiencing ST-segment elevation myocardial infarction (STEMI). However, it has not been possible in living patients to accurately define the relationship between LCP and STEMI culprit lesions. Identification of LCP concentrated at the site of thrombosis would be valuable because the LCP may have been present prior to plaque rupture and thrombosis and could therefore have served as a target for preventive therapy.

Intracoronary near-infrared spectroscopy (NIRS) has recently been developed to identify LCP in patients undergoing coronary angiography (10–15). NIRS has demonstrated that culprit lesions in stabilized patients with non–ST-segment elevation acute coronary syndrome and in patients with stable angina frequently contain LCP (15). In the present study, the culprit lesion in STEMI patients was evaluated with combined NIRS and intravascular ultrasound (IVUS) imaging after restoration of arterial flow, but before alteration of the plaque by stenting. To assess the sensitivity and specificity of the NIRS-IVUS findings, a case-control analysis was performed in which the results obtained at STEMI culprit sites were compared with those in nonculprit portions of the STEMI culprit artery and in autopsy control segments.

Methods

Study population

This study was conducted in consecutive STEMI patients referred acutely for primary percutaneous coronary intervention (PCI) at the Frederik Meijer Heart and Vascular Institute (Spectrum Health, Grand Rapids, Michigan). For all cases, 1 of the authors (R.D.M.) was either the primary PCI operator or an adviser for NIRS-IVUS imaging. Consecutive patients meeting the following criteria were included: acute chest pain; electrocardiographic findings of STEMI; myocardial infarction by the universal definition (16); and NIRS-IVUS performed within the culprit vessel after establishment of TIMI (Thrombolysis In Myocardial Infarction) flow grade 3 (17), but prior to stent placement. Patients were excluded if hemodynamic instability was present, STEMI was attributable to stent thrombosis, or culprit NIRS images were uninterpretable. The decision to use NIRS-IVUS was made by the operator during the procedure. The study was approved by the Institutional Review Board of Spectrum Health, and all patients provided written informed consent.

Invasive coronary angiography and primary PCI

The culprit lesion, identified angiographically by the physician performing PCI, corresponded to the area of ischemia indicated by ST-segment elevation. The initial angiogram was used to define the proximal margin of the culprit lesion. A guidewire was then advanced into the distal segment of the culprit vessel. Routine measures to establish TIMI flow grade 3 (aspiration thrombectomy and/or balloon angioplasty) were performed at the discretion of the PCI operator and preceded NIRS-IVUS imaging. If balloon angioplasty was performed, a small balloon (balloon diameter to reference vessel diameter: 0.7 ± 0.1) was inflated briefly to nominal pressure to minimize alteration of the culprit plaque while still achieving vessel patency and TIMI flow grade 3.

NIRS-IVUS imaging

NIRS-IVUS imaging (TVC Imaging System, InfraReDx, Burlington, Massachusetts) was performed after TIMI flow grade 3 was established. The NIRS-IVUS catheter was advanced beyond the culprit lesion and motorized pullback was performed at 0.5 mm/s (18). After NIRS-IVUS imaging, stents were placed in all but 1 patient who was referred for bypass surgery for multivessel disease. IVUS provided data useful for selection of optimal stent diameter and length.

NIRS-IVUS analysis

NIRS images were interpreted as previously described (10–15,18). For NIRS-IVUS analysis, the STEMI culprit segment was defined as the first 10 mm of artery distal to the proximal margin of the culprit lesion. The vessel outside these margins was divided into nonoverlapping 10-mm nonculprit segments. To quantify the amount of lipid present, we calculated the lipid core burden index (LCBI), the fraction of pixels indicating lipid within a region multiplied by 1,000 (10–15,18). Each 10-mm culprit and nonculprit segment was scanned for the maximum LCBI in any 4-mm region (maxLCBI4mm), as previously described (10,14).

The NIRS-IVUS catheter provided coregistered IVUS data for all NIRS imaging. IVUS analysis was performed off-line by the Atherosclerosis Imaging Core Laboratory of the Cleveland Clinic according to previously published methodology and expert consensus recommendations (19–24). IVUS parameters assessed included plaque burden (PB) and calcification (Online Appendix).

Control groups

In the primary analysis, the findings in the 20 STEMI culprit segments were compared with findings in all 87 nonculprit segments of the 20 culprit vessels. Additional comparisons were performed between STEMI culprit segments and autopsy specimens selected for their LCP findings on histologic analysis. Because prior autopsy studies have demonstrated LCP to be present at STEMI culprit sites (2–8), it was hypothesized that NIRS findings in STEMI culprit segments would be similar to NIRS findings in autopsy specimens with very large LCP by histology (histology-positive, n = 19) and differ from those in autopsy specimens free of large LCP by histology (histology-negative, n = 279). We also compared NIRS findings within STEMI culprit segments to NIRS findings in autopsy specimens from individuals with no clinical history of coronary artery disease (Online Appendix).

Statistical analysis

MaxLCBI4mm was the primary measure of interest in this study. STEMI culprit segments were compared to all nonoverlapping 10-mm segments in control groups. Descriptive statistics were used to summarize MaxLCBI4mm, PB, and the percentage of IVUS images containing calcium. To test the ability of maxLCBI4mm, PB, and calcification to differentiate STEMI culprit segments from nonculprit segments within the culprit artery, receiver-operating characteristic analyses and calculations of sensitivity, specificity, and positive and negative predictive values were performed. A similar analysis was performed to determine the ability of maxLCBI4mm, PB, and calcification to identify STEMI culprit segments when admixed with histology-negative autopsy specimens. Logistic regression modeling was used to determine the relative contribution of each measure (maxLCBI4mm, PB, and calcification) to identification of culprit lesion status. Data analysis was performed (by K.W.) at the Atherosclerosis Imaging Core Laboratory of the Cleveland Clinic. Additional statistical details are presented in the Online Appendix.

Results

Study population

Between January 20 and June 12, 2012, NIRS-IVUS was performed within the culprit vessel of 23 patients experiencing STEMI. Of these, 1 patient was excluded because the clinical presentation was attributable to very late stent thrombosis and 2 patients were excluded because of uninterpretable NIRS data. The analysis was performed in the remaining 20 patients, all of whom had a single culprit lesion identified by angiography (Online Table 1). Culprit lesion location, initial TIMI flow grades, and methods used to establish TIMI flow grade 3 prior to NIRS-IVUS imaging are presented in Online Table 1.

NIRS findings in STEMI culprit lesions and control groups

As shown in Figures 1 and 2, NIRS frequently identified a large, nearly circumferential LCP at the STEMI culprit site. The histologic basis of such large yellow spots on the chemogram is demonstrated in Figure 3A. In Figure 3B, chemograms from STEMI patients are compared to chemograms from the autopsy control groups.

(A) The relationship of yellow spots on the chemogram to histology. The top chemogram was obtained in a STEMI culprit vessel. The lower chemogram, obtained in an autopsy specimen, shows 2 yellow spots similar to those observed in STEMI culprits. Histologic cross sections demonstrate both yellow spots on the lower chemogram correspond with large lipid cores. (B) Chemograms in STEMI culprit vessels versus chemograms from autopsy control groups. NIRS evidence of LCP is extensive in STEMI culprit segments (green arrow = proximal angiographic culprit margin) and in histology-positive autopsy specimens. In contrast, NIRS evidence of LCP is sparse in histology-negative autopsy specimens and in those with no clinical history of CAD. CAD = coronary artery disease; other abbreviations as in Figure 1.

(A) The ability of NIRS and IVUS to distinguish culprit segments from nonculprit segments in the STEMI culprit vessel. MaxLCBI4mm(red), PB (green), and calcification (black) by IVUS are shown. MaxLCBI4mm was significantly more discriminatory than calcification (AUC: 0.90 vs. 0.72; p = 0.016) and performed similar to PB (AUC: 0.90 vs. 0.86; p = 0.44). (B) The ability of NIRS and IVUS to identify STEMI culprit segments when admixed with histology-negative autopsy specimens. MaxLCBI4mm(red), PB (green), and calcification (black) by IVUS are shown. MaxLCBI4mm was significantly more discriminatory at identifying STEMI culprit segments than were PB (AUC: 0.97 vs. 0.83; p = 0.015) or calcification (AUC: 0.97 vs. 0.79; p = 0.002). PB and calcification were not significantly different (p = 0.17). AUC = area under curve; ROC = receiver-operating curve; other abbreviations as in Figures 1, 2, and 4.

IVUS findings

STEMI culprit segments had a greater PB and more frequent calcification than did nonculprit segments in the culprit artery or histology-negative autopsy specimens (Online Table 2). With respect to differentiating culprit segments from nonculprit segments in the STEMI culprit artery, maxLCBI4 mm performed similar to PB (AUC: 0.90 vs. 0.86; p = 0.44). Whereas both maxLCBI4 mm and PB were able to identify STEMI culprits segments against a background of NIRS findings from histology-negative autopsy specimens, the AUC for maxLCBI4 mm was significantly higher than that for PB (0.97 vs. 0.83, p = 0.015) (Fig. 5). MaxLCBI4mm was significantly more discriminatory at identifying STEMI culprits than was calcification by IVUS when tested against both control groups (Fig. 5). Although maxLCBI4mm, PB, and calcification were all significantly associated with STEMI culprit segments by univariable analysis, maxLCBI4 mm emerged as the only significant predictor by multivariable analysis (Online Tables 4 and 5).

Discussion

The primary finding of the present study is the detection by NIRS imaging of a signature of the culprit plaques causing STEMI, a leading cause of death and disability throughout the world (1). These novel in vivo findings are in accordance with extensive ex vivo autopsy data (2–8), and they complement in vivo observations documenting the presence of thrombus at the culprit site in STEMI patients (9). Most importantly for predictive and preventive purposes, it is possible that the large LCP observed at STEMI culprit sites were present and detectable before thrombus formation and the acute coronary event.

The finding of extensive LCP at STEMI culprit sites was made possible by use of a novel NIRS-IVUS technology in an acute setting. The NIRS system, developed specifically to detect LCP within the coronary wall, has been extensively validated in autopsy specimens and is cleared by the U.S. Food and Drug Administration for this purpose (10,25). Even though the NIRS system has been used in over 3,000 patients worldwide, the present study is the first report of its use in a consecutive series of STEMI patients with minimally altered culprit plaques. The STEMI culprit lesion, which is easily identified by the sudden occurrence of a focal, occlusive thrombus, is particularly well suited as a standard to detect a signature of a plaque prone to rupture and thrombosis.

NIRS signature of STEMI culprit lesions

The present in vivo findings are in agreement with multiple autopsy studies documenting that rupture of a large LCP is the most frequent cause of a fatal myocardial infarction (2–8). The novel NIRS capability makes it possible to extend these autopsy findings into patients undergoing stenting. A novel observation in the present study, evident from visual examination of the STEMI culprit chemograms, is that the lipid core at the culprit site is often circumferential in nature, and sometimes quite narrow—features captured by the maxLCBI4mm measure. Our finding of circumferential LCP at many STEMI culprit sites is in accord with results of an in vivo optical coherence tomography study (26), post-mortem NIRS findings in a patient with sudden cardiac death (12), and with in vivo results obtained using other intravascular imaging techniques that have reported evidence of LCP at STEMI culprit sites (27–29).

Although our findings are concordant with previous imaging studies, they differ in several important aspects. First, previous studies with optical coherence tomography (26) and virtual histology-IVUS (28) did not compare culprit findings with control data for other sections of the culprit artery. Second, although the angioscopy (29) and grayscale-IVUS studies reported culprit artery control data, the difference between findings for culprit and control lesion was not as marked as for NIRS. Third, none of the previous imaging studies (26–29) include findings in autopsy specimens in which a histologic gold standard is available.

The control data for this study demonstrate that a threshold maxLCBI4mm >400 has a 98% specificity for identification of STEMI culprit sites admixed with sites from autopsy specimens free of large LCP. This high specificity was achieved while maintaining a sensitivity of 85%. The 98% specificity applies to this cross-sectional comparison of culprit sites with autopsy control lesions; the specificity of the signature for prospective identification of lesions likely to cause a STEMI, or other coronary event, can only be determined in a longitudinal prospective clinical study. The single STEMI case that failed to show lipid at the culprit site was found to have a calcified nodule—a recognized infrequent cause of myocardial infarction (23). MaxLCBI4mm also differed between the STEMI culprit sites and nonculprit portions of the same vessel, indicating the focal nature of coronary atherosclerotic lesions.

The finding of a NIRS signature at STEMI culprit sites that differs significantly from findings in control segments contributes to the broader effort of detecting the signature of a vulnerable plaque, defined as a plaque prone to disruption and thrombosis (30). The signature identified for STEMI culprit lesions in the present study has also been observed in other coronary conditions—non-STEMI, unstable angina, and even stable angina (15,25). These observations are in accord with the concept that rupture of a vulnerable plaque may produce STEMI in some cases; sudden death, non-STEMI, unstable angina, or stable angina in others; or may, in a less obvious yet still harmful manner, simply contribute to asymptomatic plaque progression (31). The finding by NIRS of significant amounts of LCP in non-STEMI, unstable angina, and stable angina culprits supports the concept that the STEMI culprit NIRS signature in a broader sense may be considered the signature of a plaque prone to rupture (15).

IVUS features of STEMI culprit lesions

The findings of the present cross-sectional study provide support for the concept established by 2 recent prospective IVUS-based studies that identification of vulnerable plaques is possible. The PROSPECT (Providing Regional Observations To Study Predictors of Events in the Coronary Tree: An Imaging Study in Patients With Unstable Atherosclerotic Lesions) study identified PB >70% as the leading multivariable predictor of subsequent coronary events (32). The PREDICTION (Prediction of Progression of Coronary Artery Disease Using Vascular Profiling of Shear Stress and Wall Morphology) study confirmed that baseline PB is a predictor of lesion progression (33). Consistent with these studies, we observed PB was significantly increased at STEMI culprit sites; however, multivariable analysis indicated that PB was not needed to enhance the highly accurate identification of STEMI culprit sites provided by NIRS alone. Furthermore, maxLCBI4mm is automatically computer-generated for the segment analyzed and does not require time-consuming analysis by an expert reader.

Implications for treatment

These data provide support for the next step in evaluation of the NIRS signature of culprit lesions, which is the conduct of a prospective prediction study (34). If NIRS is prospectively validated as a reliable predictor of clinical events, randomized studies of multiple promising systemic and local therapies could be conducted. The recent failure of several outcome studies of high-density lipoprotein–raising therapy (35) demonstrates the need for a more effective selection of agents to undergo such trials. The YELLOW (Reduction in Yellow Plaque by Aggressive Lipid Lowering Therapy) study (36) recently demonstrated that NIRS could detect a reduction of coronary LCP with high-dose rosuvastatin therapy. Promising agents such as the PCSK9 inhibitors (37) and anti-inflammatory agents (4) could be tested in a similar fashion.

Study limitations

First, the primary findings are based on only 20 STEMI patients at a single center and only culprit vessels were analyzed; however, the results are concordant with previous pathologic data and large differences were detected between STEMI culprit and control lesions. Second, because maxLCBI4mm >400 as a threshold to detect STEMI culprits was selected after examination of the data, a prospective study using the threshold is needed. Third, NIRS requires invasive study and is not suitable for screening of the general population in which most coronary events occur. For this reason, an initial clinical application of NIRS could be for secondary prevention in those undergoing catheterization for other indications. If secondary prevention could be demonstrated, primary prevention strategies could be evaluated by using NIRS for invasive confirmation of plaques suspected to be vulnerable by noninvasive testing (38,39). Fourth, the majority of STEMI culprit lesions were in the right coronary artery; it is unknown if the present findings would be altered in a population with predominantly left coronary artery culprits. Finally, culprit lesion PB may have been reduced by spontaneous embolization of friable plaque contents after plaque rupture or by balloon angioplasty before imaging.

Conclusions

A NIRS signature of the plaques causing STEMI has been detected in vivo. This signature accurately detects STEMI culprit lesions admixed with nonculprit segments of the culprit vessel or with segments from autopsy control lesions. These data support conduct of a long-term, large prospective study to test the hypothesis that intracoronary NIRS can provide accurate, site-specific prediction that a given plaque is likely to cause a coronary event and thereby facilitate development of more effective preventive therapies.

Acknowledgments

The authors would like to thank the staff of Spectrum Health for assistance in the study of the STEMI cases, Stacie VanOosterhout, MEd, for study management, and Craig Balog, BS, for assistance with data analysis.

Appendix

Appendix

For supplemental tables, please see the online version of this paper.

Footnotes

Dr. Madder has received speaker honoraria from Infraredx and consulting fees from St. Jude Medical. Dr. Madden, Mr. Hendricks, and Dr. Sum are employees of Infraredx, the company that developed the NIRS-IVUS instrument. Dr. Goldstein has received consulting fees from and has stock ownership in Infraredx. Dr. Kini has received research grant support from Infraredx and honoraria from Medscape and St. Jude Medical. Dr. Sharma has served on the Speakers' Bureaus of Abbott Vascular, Boston Scientific Corporation, DSI/Lilly, The Medicine Co., and Angioscore; and has received research grant support from Infraredx. Dr Sharma is affiliated with Abbott Vascular. Dr. Rizik has received research grant support from Infraredx. Dr. Brilakis has received honoraria from Bridgepoint Medical, St. Jude Medical, and Terumo; has received a research grant from Guerbet and Infraredx; and his spouse is an employee of Medtronic. Dr. Shunk has received research grants from Infraredx, Gilead, Abbott Vascular, and Siemens Medical Systems; and is a principal partner in Revascular Therapeutics. Dr. Weisz has received consulting fees from Infraredx. Dr. Petersen has received research grant support from Infraredx. Dr. Nicholls has received research support from Infraredx, AstraZeneca, Resverlogix, Eli Lilly, Novartis, Anthera, and Roche; and consulting fees from Merck, AstraZeneca, Takeda, Roche, Omthera, CSL Behring, and Boehringer Ingelheim. Dr. Maehara has received speakers' fees from St. Jude Medical; and a research grant from Boston Scientific Corporation and Infraredx. Dr. Mintz has received grant support from Infraredx; and grant support and honoraria from Volcano, Boston Scientific, and St. Jude Medical. Dr. Stone has received consulting fees from Infraredx. Dr. Muller is an employee of, with stock ownership in, Infraredx, the company that developed the NIRS-IVUS instrument. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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